This is an application for a 5-year K01 award from NIAID with an emphasis particularly relevant to NIAID's goals (NOT-AI-04-033) of fostering the career development of young scientists in infectious diseases and AIDS epidemiology and outcomes research. Bryan Lau, Ph.D., will apply rigorous epidemiological and biostatistical methods to address three major research aims that are highly relevant to the current HIV care. While effective therapies have greatly reduced the mortality and morbidity due to HIV, current concerns regarding the optimization of therapy and the changes in mortality outcomes remain. Current therapeutic guidelines for HIV recommend initiating a HAART regimen at CD4 counts below 200 cells/uL and consider nitiating between 200 to 350 cells/uL Despite the therapeutic guidelines, individuals above 200 cells/uL do progress to AIDS and death. Clinical cohort studies may be useful for addressing questions related to optimization of therapy and the changes in mortality that have occurred due to therapy. However, clinical cohort studies have unstructured visit schedules allowing for individuals to potentially self-select for more frequent health-care utilization whereas the "classical" cohort individuals are followed at set time-intervals. Although classical cohort study designs may not capture the fullest extent of the information with a set interval between study visits as the interval is arbitrary and not based on health care needs. The goal of this research project is to: 1) determine whether biological markers other than CD4 counts and HIV RNA levels could potentially be used to further target therapy towards individuals that need to initiate treatment and whether these markers may be utilized in monitoring treatment response;2) quantify the changes in cause-specific mortality risk since the introduction of effective therapies;and 3) to compare potential differences in results between interval-based (classical) and clinic-based cohort studies. These goals will be accomplished by utilizing two ongoing HIV cohorts: the Johns Hopkins HIV Clinical Cohort and AIDS Link to Intravenous Experience (ALIVE). These aims have important clinical and public health significance in that individuals may be better targeted for initiation of therapy and monitored for therapy effectiveness. Additionally, identifying changes in cause-specific mortality may help identify potential areas that require attention that may not traditionally be considered HIV-related. The K01 will provide the protected time for Dr. Lau to gain the additional mentored research experience, coursework, and involvement in HIV-related seminars and other forums that will substantially augment Dr. Lau's current research capabilities in biostatistics and epidemiology, enable him to gain an in-depth knowledge of the increasingly complex issues in clinical HIV research, and integrate these disciplines in a productive and independent research career.